MYO10 drives genomic instability and inflammation in cancer.
MYO10 drives genomic instability and inflammation in cancer.
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DOI：
10.1126/sciadv.abg6908
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发表时间：
2021-09-17
期刊：
影响因子：
13.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Mayca Pozo F;Geng X;Tamagno I;Jackson MW;Heimsath EG;Hammer JA;Cheney RE;Zhang Y
这项研究揭示了对癌症发展的见解，并可能导致发现癌症免疫治疗的生物标志物。基因组的不稳定性是人类癌症的一个标志，但其潜在的机制仍然知之甚少。在这里，我们报告了细胞质非常规肌球蛋白X（MYO 10）调节基因组稳定性，通过它介导癌症中的炎症。MYO 10是一种不稳定的蛋白质，其经历泛素缀合酶H7（UbcH 7）/β-转导蛋白重复序列包含蛋白1（β-TrCP 1）依赖性降解。MYO 10在人类和小鼠肿瘤中均上调，其表达水平易导致肿瘤进展和对免疫治疗的反应。过表达MYO 10增加了基因组的不稳定性，提高了环GMP-AMP合酶（cGAS）/干扰素基因（STING）依赖性炎症反应的刺激因子，并加速了小鼠的肿瘤生长。相反，MYO 10的消耗改善了基因组不稳定性并减少了炎症信号传导。此外，抑制炎症或破坏Myo 10显著抑制了小鼠中人类和小鼠乳腺肿瘤的生长。我们的数据表明MYO 10通过诱导基因组不稳定性促进肿瘤进展，这反过来又为免疫检查点阻断创造了免疫原性环境。
This study reveals insights into cancer development and may result in the discovery of a biomarker for cancer immunotherapy. Genomic instability is a hallmark of human cancer; yet the underlying mechanisms remain poorly understood. Here, we report that the cytoplasmic unconventional Myosin X (MYO10) regulates genome stability, through which it mediates inflammation in cancer. MYO10 is an unstable protein that undergoes ubiquitin-conjugating enzyme H7 (UbcH7)/β-transducin repeat containing protein 1 (β-TrCP1)–dependent degradation. MYO10 is upregulated in both human and mouse tumors and its expression level predisposes tumor progression and response to immune therapy. Overexpressing MYO10 increased genomic instability, elevated the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)–dependent inflammatory response, and accelerated tumor growth in mice. Conversely, depletion of MYO10 ameliorated genomic instability and reduced the inflammation signaling. Further, inhibiting inflammation or disrupting Myo10 significantly suppressed the growth of both human and mouse breast tumors in mice. Our data suggest that MYO10 promotes tumor progression through inducing genomic instability, which, in turn, creates an immunogenic environment for immune checkpoint blockades.
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影响因子：
29.4
作者：
Boland CR;Goel A
通讯作者：
Goel A
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
7.8
作者：
Fonseca, Cindy L.;Malaby, Heidi L. H.;Stumpff, Jason
通讯作者：
Stumpff, Jason
影响因子：
5.2
作者：
Arico, Eleonora;Castiello, Luciano;Belardelli, Filippo
通讯作者：
Belardelli, Filippo
影响因子：
1.6
作者：
Fricke J;Mambetsariev I;Pharaon R;Subbiah S;Rajurkar S;Salgia R
通讯作者：
Salgia R